The present invention relates to substituted tetrahydro-naphthalenes and analogous compounds, to processes for their preparation and to their use in pharmaceuticals.
7-(polysubstituted pyridyl)-6-heptenoates for the treatment of arteriosclerosis, lipoproteinaemia and hyperproteinaemia are known from the publication U.S. Pat. No. 5,169,857-A2. In addition, the preparation of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates is described in the publication EP-325 130-A2.
The present invention relates to substituted tetrahydro-naphthalenes and analogous compounds of the general formula (I), 
in which
A represents cycloalkyl having 3 to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or
xe2x80x83represents a 5- to 7-membered saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 4 heteroatoms selected from the group consisting of S, N and/or O,
xe2x80x83where aryl and the abovementioned heterocyclic ring systems may optionally be substituted up to 5 times by identical or different substituents selected from the group consisting of cyano, halogen, nitro, carboxyl, hydroxyl, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy having in each case up to 7 carbon atoms, or by a group of the formula xe2x80x94NR3R4 
xe2x80x83in which
R3 and R4 are identical or different and each represents hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
D represents a radical of the formula 
xe2x80x83in which
R5, R6 and R9 independently of one another each represent cycloalkyl having 3 to 6 carbon atoms, or
xe2x80x83aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic heterocycle having up to 4 heteroatoms selected from the group consisting of S, N and/or O,
xe2x80x83where the cycles are optionally, in the case of the nitrogen-containing rings also via the N-function, substituted up to 5 times by identical or different constituents selected from the group consisting of halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms or by an optionally benzo-fused aromatic 5- to 7-membered heterocycle having up to 3 heteroatoms selected from the group consisting of S, N and/or O,
xe2x80x83and/or by a group of the formula xe2x80x94OR10, xe2x80x94SR11, xe2x80x94SO2R12 or xe2x80x94NR13R14,
xe2x80x83in which
R10, R11 and R12 independently of one another each represent aryl having 6 to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents selected from the group consisting of phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,
R13 and R14 are identical or different and are as defined above for R3 and R4,
xe2x80x83or
R5 and/or R6 represents/represent a radical of the formula 
R7 represents hydrogen, halogen or methyl,
xe2x80x83and
R8 represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula xe2x80x94NR15R16,
xe2x80x83in which
R15 and R16 are identical or different and are as defined above for R3 and R4,
xe2x80x83or
R7 and R8 together form a radical of the formula xe2x95x90O or xe2x95x90NR17,
xe2x80x83in which
R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain, having in each case up to 8 carbon atoms, which is optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and each represents a straight-chain or branched alkylene chain having up to 8 carbon atoms,
xe2x80x83or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents a xe2x80x94NR18 group,
xe2x80x83in which
R18 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
E represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl, which is optionally substituted by halogen or trifluoromethyl,
R1 and R2 together form a straight-chain or branched alkylene chain, having up to 7 carbon atoms, which has to be substituted by a carbonyl group and/or by a radical of the formula 
xe2x80x83in which
a and b are identical or different and each represents a number 1, 2 or 3,
R19 represents hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched silylalkyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or by phenyl which for its part may be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl, and alkyl is optionally substituted by a group of the formula xe2x80x94OR22,
xe2x80x83in which
R22 represents straight-chain or branched acyl having up to 4 carbon atoms or benzyl,
xe2x80x83or
R19 represents straight-chain or branched acyl having up to 20 carbon atoms or benzoyl which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or straight-chain or branched fluoracyl having up to 8 carbon atoms and 9 fluorine atoms,
R20 and R21 are identical or different and each represents hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
xe2x80x83or
R20 and R21 together form a 3- to 6-membered carbocycle,
and the alkylene chain which is formed by R1 and R2 is optionally substituted up to 6 times, optionally also geminally, by identical or different substituents selected from the group consisting of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy having in each case 3 to 7 carbon atoms, by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms which for its part is substituted up to 2 times by identical or different substituents selected from the group consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl and carboxyl having in each case up to 4 carbon atoms and phenyl which for its part may be substituted by halogen, trifluoromethyl or trifluoromethoxy,
and/or the alkylene chain which is formed by R1 and R2 is optionally substituted, also geminally, up to 5 times by identical or different substituents selected from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl, which for their part are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,
and/or the alkylene chain formed by R1 and R2 is optionally substituted by a radical of the formula 
xe2x80x83in which
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R23 and R24 are identical or different and each represents hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted up to 2 times by identical or different substituents selected from the group consisting of halogen, trifluoromethyl, cyano, phenyl and nitro,
and/or the alkylene chain formed by R1 and R2 is optionally substituted by a spiro-linked radical of the formula 
xe2x80x83in which
W represents either an oxygen or a sulphur atom,
Y and Yxe2x80x2 together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4, 5, 6 or 7,
f represents a number 1 or 2,
R25, R26, R27, R28, R29, R30 and R31 are identical or different and each represents hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
xe2x80x83or
R25 and R26 or R27 and R28, in each case together, form a straight-chain or branched alkyl chain having up to 6 carbon atoms,
xe2x80x83or
R25 and R26 or R27 and R28, in each case together, form a radical of the formula 
xe2x80x83in which
W is as defined above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
R32 and R33 together form a 3- to 7-membered heterocycle which contains an oxygen or sulphur atom or a group of the formula SO, SO2 or xe2x80x94NR34,
xe2x80x83in which
R34 represents hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
and stereoisomers, stereoisomer mixtures and salts thereof.
The compounds according to the invention may also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, preference is given to physiologically acceptable salts. Physiologically acceptable salts of the compounds according to the invention may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, titaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts may likewise be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particular preference is given, for example, to sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds according to the invention may exist in stereoisomeric forms which are either like image or mirror image (enantiomers), or which are not like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereomerically uniform components in a known manner.
In the context of the invention, heterocycle, optionally benzo-fused, generally represents a saturated, partially saturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered, heterocycle which may contain up to 4 heteroatoms selected from the group consisting of S, N and/or O. Examples include: indolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Preference is given to quinolyl, furyl, pyridyl and thienyl.
Preference is given to the compounds according to the invention of the general formula (I), in which
A represents cyclopentyl or represents cyclohexyl, or represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholinyl, each of which is optionally substituted up to 2 times by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy having in each case up to 6 carbon atoms,
D represents a radical of the formula 
xe2x80x83in which
R5, R6 and R9 independently of one another each represent cyclopropyl, cyclopentyl or cyclohexyl, or
xe2x80x83phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
xe2x80x83where the cycles are optionally substituted up to 3 times, in the case of the nitrogen-containing rings also via the N-function, by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, trifluoromethyl-substituted phenyl and phenyl,
xe2x80x83and/or are substituted by a group of the formula xe2x80x94OR10, xe2x80x94SR11 or xe2x80x94SO2R12,
xe2x80x83in which
R10, R11 and R12 are identical or different and are each phenyl which for its part is substituted up to 2 times by identical or different substituents selected from the group consisting of phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms,
xe2x80x83or
R5 and/or R6 represents/represent a radical of the formula 
R7 represents hydrogen, fluorine, chlorine or bromine,
xe2x80x83and
R8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula xe2x80x94NR15R16,
xe2x80x83in which
R15 and R16 are identical or different and each represents hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
xe2x80x83or
R7 and R8 together form a radical of the formula xe2x95x90O or xe2x95x90NR17,
xe2x80x83in which
R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain, having in each case up to 6 carbon atoms, which is optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and each represents a straight-chain or branched alkylene chain having up to 6 carbon atoms,
xe2x80x83or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents a group of the formula xe2x80x94NR18xe2x80x94,
xe2x80x83in which
R18 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or straight-chain or branched alkyl, having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,
R1 and R2 together form a straight-chain or branched alkylene chain, having up to 6 carbon atoms, which has to be substituted by a carboxyl group and/or by a radical of the formula 
xe2x80x83in which
b represents a number 1, 2 or 3,
R19 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by phenyl, which for its part may be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,
xe2x80x83and alkyl is optionally substituted by a group of the formula xe2x80x94OR22,
xe2x80x83in which
R22 represents straight-chain or branched acyl having up to 3 carbon atoms or benzyl,
xe2x80x83or
R19 represents straight-chain or branched acyl having up to 18 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or straight-chain or branched fluoracyl having up to 6 carbon atoms,
R20 and R21 are identical or different and are each hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
xe2x80x83or
R20 and R21 together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring,
and the alkylene chain which is formed by R1 and R2 is optionally substituted up to 5 times, optionally also geminally, by identical or different substituents selected from the group consisting of trifluoromethyl, hydroxyl, carboxyl, azido, fluorine, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to about 5 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms which for its part is substituted up to 2 times by identical or different substituents selected from the group consisting of hydroxyl, benzyloxy, benzoyl, straight-chain or branched alkoxy or oxyacyl having in each case up to 3 carbon atoms, trifluoromethyl and/or phenyl which for its part may be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
and/or the alkylene chain formed by R1 and R2 is optionally, also geminally, substituted up to 4 times by identical or different substituents selected from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl, which for their part are optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or nitro,
and/or is optionally substituted by a radical of the formula 
xe2x80x83in which
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R23 and R24 are identical or different and each represents hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl, having up to 5 carbon atoms, phenyl or benzyl, which is optionally substituted by fluorine, chlorine, bromine, phenyl or trifluoromethyl,
and/or the alkylene chain formed by R1 and R2 is optionally substituted by a spiro-linked radical of the formula 
xe2x80x83in which
W is either an oxygen or a sulphur atom,
Y and Yxe2x80x2 together form a 2- to 5-membered straight-chain or branched alkyl chain,
e represents a number 1, 2, 3, 4, 5 or 6,
R25, R26, R27 and R28 are identical or different and each represents hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms,
xe2x80x83or
R25 and R26 or R27 and R28, in each case together, form a straight-chain or branched alkyl chain having up to 5 carbon atoms or
R25 and R26 or R27 and R28, in each case together, form a radical of the formula 
xe2x80x83in which
W is as defined above,
g represents a number 1, 2, 3, 4, 5 or 6,
R32 and R33 together form a 5- to 6-membered heterocycle which contains an oxygen or sulphur atom or a group of the formula NH or NCH3,
and stereoisomers, stereoisomer mixtures and salts thereof.
Particular preference is given to compounds of the general formula (I) according to the invention in which
A represents phenyl, pyridyl or thienyl, which are optionally substituted up to 2 times by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms,
D represents a radical of the formula 
xe2x80x83in which
R6 and R9 independently of one another each represent cyclopropyl, cyclopentyl or cyclohexyl, or
xe2x80x83phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
xe2x80x83where the cycles are optionally substituted up to 3 times, in the case of the nitrogen-containing rings also via the N-function, by identical or different substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl
xe2x80x83and/or substituted by a group of the formula xe2x80x94OR10, xe2x80x94SR11 or xe2x80x94SO2R12,
xe2x80x83in which
R10, R11 and R12 are identical or different and each represents phenyl which for its part is substituted up to 2 times by identical or different substituents selected from the group consisting of phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms,
xe2x80x83or
R6 represents a radical of the formula 
R7 represents hydrogen or fluorine,
xe2x80x83and
R8 represents hydrogen, fluorine, chlorine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl having in each case up to 4 carbon atoms or a radical of the formula xe2x80x94NR15R16,
xe2x80x83in which
R15 and R16 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
xe2x80x83or
R7 and R8 together form a radical of the formula xe2x95x90O or xe2x95x90NR17,
xe2x80x83in which
R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain, having in each case up to 5 carbon atoms, which is optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and each represents a straight-chain or branched alkylene chain having up to 3 carbon atoms,
xe2x80x83or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents a group of the formula xe2x80x94NR18,
xe2x80x83in which
R18 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or
xe2x80x83represents straight-chain or branched alkyl, having up to 4 carbon atoms, which is optionally substituted by hydroxyl,
R1 and R2 together form a straight-chain or branched alkylene chain, having up to 5 carbon atoms, which has to be substituted by a carbonyl group and/or a radical of the formula 
xe2x80x83in which
R19 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 6 carbon atoms or straight-chain or branched alkyl, having up to 4 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 3 carbon atoms or by phenyl, which for its part may be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,
xe2x80x83and alkyl is optionally substituted by a group of the formula xe2x80x94OR22,
xe2x80x83in which
R22 is straight-chain or branched acyl having up to 3 carbon atoms or benzyl,
xe2x80x83or
R19 is straight-chain or branched acyl having up to 15 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or straight-chain or branched fluoracyl having up to 4 carbon atoms,
and the alkylene chain formed by R1 and R2 is optionally substituted up to 4 times, optionally also geminally, by identical or different substituents selected from the group consisting of fluorine, hydroxyl, trifluoromethyl, carboxyl, azido, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to 4 carbon atoms or by straight-chain or branched alkyl, having up to 4 carbon atoms, which for its part is substituted up to 2 times by identical or different constituents selected from the group consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl, methoxy, oxyacetyl and/or phenyl which for its part may be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
and/or the alkylene chain which is formed by R1 and R2 is optionally substituted, also geminally, up to 4 times by identical or different substituents selected from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by fluorine, trifluoromethyl, trifluoromethoxy or nitro,
and/or is optionally substituted by a radical of the formula 
xe2x80x83in which
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R23 and R24 are identical or different and each represents hydrogen, cyclopropyl, cyclopentyl, benzyl, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl which is optionally substituted by fluorine, chlorine or bromine,
and/or the alkylene chain formed by R1 and R2 is optionally substituted by a spiro-linked radical of the formula 
xe2x80x83in which
W represents either an oxygen or a sulphur atom,
Y and Yxe2x80x2 together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4 or 5,
R25, R26, R27 and R28 are identical or different and each represents hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
xe2x80x83or
R25 and R26 or R27 and R28, in each case together, form a straight-chain or branched alkyl chain having up to 4 carbon atoms,
xe2x80x83or
R25 and R26 or R27 and R28, in each case together, form a radical of the formula 
xe2x80x83in which
W is as defined above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
and stereoisomers, stereoisomer mixtures and salts thereof.
Very particular preference is given to the compounds of the general formula (I) according to the invention in which
A represents optionally fluorine-substituted phenyl, in particular 4-fluorophenyl,
xe2x80x83and
D represents a radical of the formula 
xe2x80x83in which
R6 represents phenyl or trifluoromethyl-substituted phenyl, preference being given to trifluoromethyl-substituted phenyl,
R7 represents hydrogen,
R8 represents hydrogen, fluorine, methoxy or hydroxyl, preference being given to fluorine,
xe2x80x83or
R7 and R8 together form a carbonyl group,
E represents cyclopropyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl, having up to 4 carbon atoms, which is optionally substituted by hydroxyl,
xe2x80x83and
R1 and R2 together represent a radical of the formula 
xe2x80x83in which
R19 represents hydrogen,
and stereoisomers, stereoisomer mixtures and salts thereof.
The compounds of the general formula (I) can be prepared when
[A] compounds of the general formula (II) 
xe2x80x83in which
A is as defined above,
R35 and R36 are identical or different and each represents straight-chain or branched alkyl having up to 4 carbon atoms,
R1xe2x80x2 and R2xe2x80x2 together represent the straight-chain or branched alkylene chain, having up to 7 carbon atoms, mentioned above under R1 and R2, which is substituted by tert-butyl-dimethyl-silanyloxy (OTBS),
xe2x80x83and
Exe2x80x2 and Exe2x80x3 together with the carbon atom to which they are attached have the range of meanings of E given above,
are initially converted by selective reduction of the aliphatic ester and subsequent reaction with compounds of general formula (III)
xe2x80x83R37-halogenxe2x80x83xe2x80x83(III)
xe2x80x83in which
R37 represents mesyl, tosyl or sulphonyl,
xe2x80x83and
Halogen represents chlorine, bromine or iodine, preferably chlorine,
in inert solvents, in the presence of a base,
into the compounds of the general formula (IV) 
xe2x80x83in which
A, Exe2x80x2, Exe2x80x3, R1xe2x80x2, R2xe2x80x2, R35 and R37 are each as defined above,
these are converted in a further step, depending on the definitions of Exe2x80x2/Exe2x80x3 given above, either by a two-fold reduction or by hydrolysis, Barton reaction and a reduction, into the compounds of the general formula (V) 
xe2x80x83in which
A, E, R1xe2x80x2 and R2xe2x80x2 are each as defined above,
the aldehydes of the general formula (VI) 
xe2x80x83in which
A, E, R1xe2x80x2 and R2xe2x80x2 are each as defined above,
are subsequently prepared by oxidation
and finally, for example by a Grignard reaction, the formyl group is converted into the radical D and the TBS group is cleaved off by customary methods,
xe2x80x83or
[B] compounds of the general formula (VI) 
xe2x80x83in which
A, E, R1xe2x80x2 and R2xe2x80x2 are each as defined above,
are initially, as described in [A], converted in a Grignard reaction with compounds of the general formula (VII)
R38xe2x80x94MgBrxe2x80x83xe2x80x83(VII)
xe2x80x83in which
R38 has the meaning of R5 and R6 given above,
in inert solvents and under an atmosphere of protective gas, into the compounds of the general formula (VIII) 
xe2x80x83in which
A, D, E, R38, R1xe2x80x2 and R2xe2x80x2 are each as defined above,
if appropriate on this stage starting from the hydroxyl function the substituents R7/R8 given under D are introduced by customary methods,
and the TBS group is subsequently cleaved off using tetrabutylammoniumfluoride in inert solvents,
xe2x80x83or
[C] compounds of the general formula (IX) 
xe2x80x83in which
A, E, R1xe2x80x2, R2xe2x80x2 and R38 are each as defined above
xe2x80x83and
R7xe2x80x2 and R8xe2x80x2 together represent the carbonyl group,
are initially reduced to the compounds of the general formula (VIII) and subsequently reacted as described under [A],
xe2x80x83or
[D] compounds of the general formula (X) 
xe2x80x83in which
x represents a number 1, 2 or 3,
xe2x80x83and
R39 and R40 are identical or different and each represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms,
it also being possible for R39 and R40 to be positioned geminally,
xe2x80x83or
R39 and R40 together form a spiro-linked carbocycle having 3 to 7 carbon atoms,
are converted with compounds of the general formula (XI) 
xe2x80x83where
E is as defined above,
xe2x80x83and
R41, R42 and R43 are identical or different and each represents straight-chain or branched alkyl having up to 10 carbon atoms,
in the presence of a metal or semi-metal reagent, initially via the intermediate stage of the general formula (XII) 
xe2x80x83in which
x, E, R39 and R40 are each as defined above,
xe2x80x83and
R44 represents metal or semi-metal derivatives, preferably those of titanium,
and by addition of the compounds of the general formula (XIII) 
xe2x80x83in which
R6 and A are each as defined above,
via intermediates of the general formula (XIV) 
xe2x80x83in which
A, E, R6, R39, R40, R44 and x are each as defined above,
into the compounds of the general formula (XV) 
xe2x80x83in which
A, E, R6, R39, R40 and x are each as defined above,
the compounds of the general formula (XVI) 
xe2x80x83in which
A, E, R6, R39, R40 and x are each as defined above,
are subsequently prepared by an elimination,
halogen compounds, for example the compounds of the general formula (XVII) and/or (XVIIa) 
xe2x80x83in which
R6, R39, R40, x, A and E are as defined above,
xe2x80x83and
Hal represents halogen, preferably chlorine or bromine,
are prepared in a further step by a halogenation
via the cyclohexadienes of the general formula (XVIII), which are formed in situ, or isomers thereof 
xe2x80x83in which
A, E, x, R6, R39 and R40 are each as defined above,
compounds of the general formula (XIX) 
xe2x80x83in which
A, E, x, R6, R39 and R40 are each as defined above
are prepared after oxidation,
furthermore, the compounds of the general formula (XX) 
xe2x80x83in which
A, E, x, R6, R39 and R40 are each as defined above,
are prepared by the reduction of the ketofunction, it also being possible to carry out the reduction stereoselectively,
the compounds of the general formula (XXI) 
xe2x80x83in which
x, A, E, R6, R39, R40, R41, R42 and R43 are each as defined above,
are subsequently prepared by silylation, for example by reaction with chlorinated or trifluoromethanesulfonyl-substituted silyl compounds (xe2x80x94SiR41R42R43)
furthermore, the compounds of the general formula (XXII) 
xe2x80x83in which
x, A, E, R6, R39, R40, R41, R42 and R43 are each as defined above,
are obtained initially by reduction of the second ketone function, as a mixture of diastereomers from which subsequently, by separation, the isomer of the general formula (XXIII) 
xe2x80x83in which
x, A, E, R6, R39, R40, R41, R42 and R43 are each as defined above are obtained,
and, if appropriate, the hydroxyl function is replaced enantioselectively by nucleophilic substitution by one of the substituents listed above under R8, thus giving compounds of the general formula (XXIV) 
xe2x80x83in which
x, A, E, R6, R8, R39, R40, R41, R42 and R43 are each as defined above
and, in a last step, the hydroxyl function is liberated according to customary methods by cleaving off the silyl protective group,
and, in the case of enantiomers/racemates, is separated by customary methods, where the structures of the general formulae (XV), (XVI), (XVII), (XVIIa) and (XVIII) may occur in isomeric forms (i.e. enantiomers, diastereomers, regioisomers).
The processes according to the invention can be illustrated by way of example by the following schemes: 
Suitable solvents for all processes are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Likewise, it is possible to employ mixtures of the abovementioned solvents. Preference is given to toluene and dichloromethane.
Suitable bases for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds, such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide, DBU or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Particular preference is given to using n-butyllithium, DBU, sodium hydride or lithium diisopropylamide.
Additionally suitable for the processes are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate or sodium bicarbonate. Particular preference is given to sodium hydride or potassium hydroxide.
Suitable organometallic reagents are, for example, systems such as Mg/bromobenzo-trifluoride and p-trifluoromethylphenyllithium.
The reductions of the compounds of the general formulae (II) and (IV) generally proceed under the following reaction conditions:
The reductions are generally carried out using reducing agents, preferably those which are suitable for reducing ketones to hydroxyl compounds. Particularly suitable for this purpose is the reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out using complex metal hydrides, such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl borohydride, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is very particularly preferably carried out using diisobutylaluminium hydride and sodium borohydride.
The reducing agent is generally employed in an amount of from 1 to 6 mol, preferably of from 1 to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds in a temperature range of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably of from xe2x88x9278xc2x0 C. to 0xc2x0 C. in the case of DIBAH, of from 0xc2x0 C. to room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of the reducing agent and the solvent.
The reduction generally proceeds at atmospheric pressure, but it is also possible to carry out the reaction at elevated or reduced pressure.
The reactions with the compounds of the general formula (III) proceed in one of the abovementioned solvents, preferably with diethyl ether.
Bases which are suitable for this purpose are generally the customary strongly basic compounds. These preferably include di- and trialkylamines, such as, for example, triethylamine, or organolithium compounds, such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Triethylamine is particularly preferably used.
Suitable bases are furthermore the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate or sodium bicarbonate. Particular preference is given to using potassium hydroxide.
The bases are generally employed in an amount of from 1 mol to 4 mol, preferably of from 1 mol to 2 mol, based on 1 mol of the compounds of the general formula (III).
The reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to room temperature, preferably of from xe2x88x9220xc2x0 C. to 0xc2x0 C.
The reaction generally proceeds at atmospheric pressure, but it is also possible to carry out the reaction at elevated or reduced pressure.
The reaction of the compounds of the general formula (V) is generally carried out under the following reaction conditions:
Solvents which are suitable for all processes are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Likewise, it is possible to use mixtures of the abovementioned solvents. Preference is given to dichloromethane.
Suitable bases for the individual steps are the customary strongly basic compounds. These preferably include pyridine or organolithium compounds, such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydride, such as sodium hydride or potassium hydride. Particular preference is given to using pyridine.
Suitable for the processes [B] and [C] are furthermore the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate or sodium bicarbonate. Particular preference is given to using sodium hydride or potassium hydroxide.
Suitable organometallic reagents are, for example, systems such as Mg/bromobenzotrifluoride and p-trifluoromethylphenyllithium.
The base is employed in an amount of from 0.1 mol to 5 mol, preferably of from 0.5 mol to 2 mol, in each case based on 1 mol of the starting material.
The reaction with Grignard reagents is generally carried out in a temperature range of from 0xc2x0 C. to 150xc2x0 C., preferably at from 25xc2x0 C. to 40xc2x0 C.
The Grignard reactions are generally carried out under atmospheric pressure. However, it is also possible to carry out the process at reduced pressure or at elevated pressure (for example in a range of from 0.5 to 5 bar).
The halogenations are generally carried out in one of the abovementioned chlorinated hydrocarbons and hydrocarbons, and preference is given to methylene chloride and toluene.
Suitable halogenating agents are, for example, diethylamino-sulphur trifluoride (DAST), morpholino-sulphur trifluoride or SOCl2.
The halogenation generally proceeds in a temperature range of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably of from xe2x88x9278xc2x0 C. to 0xc2x0 C., in each case depending on the choice of the halogenating agent and the solvent.
The halogenation generally proceeds at atmospheric pressure, but it is also possible to carry out the reaction at elevated or reduced pressure.
The protective group is generally cleaved off in one of the abovementioned alcohols and THF, preferably methanol/THF in the presence of hydrochloric acid in a temperature range of from 0xc2x0 C. to 50xc2x0 C., preferably at room temperature, and at atmospheric pressure. In particular cases, preference is given to cleaving off the protective group using tetrabutylammonium fluoride (TBAF) in THF at room temperature.
The reaction of the compounds of the general formula (VI) with the compounds of the general formula (VII) is carried out in one of the abovementioned ethers, preferably in tetrahydrofuran, under an atmosphere of protective gas in a temperature range of from xe2x88x9278xc2x0 C. to xe2x88x9210xc2x0 C., preferably at xe2x88x9225xc2x0 C.
The derivatization of the hydroxyl function into the compounds of the general formula (VIII) is carried out, for example, by oxidations, sulphonations, alkylations, hydrogenations, halogenation, Wittig/Grignard reactions and sulphur amidations.
Suitable bases for the individual steps are the customary strongly basis compounds. These preferably include organolithium compounds, such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Particular preference is given to using n-butyllithium, sodium hydride or lithium diisopropylamide.
Suitable bases are furthermore the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate or sodium bicarbonate. Particular preference is given to using sodium hydroxide or potassium hydroxide.
If appropriate, it is required to carry out some reaction steps under an atmosphere of protective gas.
The reduction of the carbonyl group in the compounds of the general formula (IX) is generally carried out under the abovementioned reaction conditions, preferably using sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene, in a temperature range of from xe2x88x9220xc2x0 C. to 140xc2x0 C., preferably of from 0xc2x0 C. to 110xc2x0 C., and at atmospheric pressure.
The reaction of the compounds of the general formulae (X) and (XI) is generally carried out under the following conditions:
Solvents which are suitable for all processes are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to employ mixtures of the abovementioned solvents. Preference is given to dichloromethane.
Suitable bases for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds, such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Particular preference is given to using n-butyllithium, sodium hydride or lithium diisopropylamide.
The base is employed in an amount of from 0.1 mol to 10 mol, preferably of from 1 mol to 5 mol, in each case based on 1 mol of the starting material.
The reaction is generally carried out in a temperature range of from xe2x88x9210xc2x0 C. to +10xc2x0 C., preferably of from 5xc2x0 C. to 10xc2x0 C. and at atmospheric pressure.
The following conditions are suitable for carrying out the process of [D]:
The reaction of the compounds of the formulae (X), (XI) and (XIII) to give compounds of the formula (XV) can be carried out without isolation of the intermediates (XII) and (XIV). Suitable reaction temperatures are between room temperature and xe2x88x9220xc2x0 C. Preferred metal or semi-metal reagents are titanium reagents, for example mixtures of titanium tetrachloride and titanium tetra-iso-propoxide, in particular in the molar ratio 3:1. Suitable solvents are the customary inert solvents, in particular dichloromethane.
The elimination to give the compounds of the formula (XVI) usually leads to a mixture of the different possible double-bond isomers. The elimination proceeds under the customary conditions, and is preferably carried out using thionyl chloride in pyridine at temperatures in the range of from xe2x88x9225 to +25xc2x0 C., preferably of from xe2x88x9210 to +10xc2x0 C.
Starting from the mixture of double-bond isomers obtained in the previous step, the halogenation to give compounds of the formula (XVII) again leads to a mixture of isomers with respect to the position of the halogen substituents and the double or single bond. Customary reagents are employed for the halogenation, preferably for allylic halogenation, and a radical initiator is employed, if appropriate. Preferred for this purpose are, for example, N-chlorosuccinimide, bromo- or N-bromosuccinimide and N-bromoacetamide. Suitable solvents are the customary inert solvents, in particular dichloromethane.
The subsequent elimination and oxidation to give the aromatic can be carried out without isolation of the intermediates, in one of the abovementioned ethers, preferably dioxane, at temperatures of from 0xc2x0 C. to 150xc2x0 C., preferably of from room temperature to 120xc2x0 C.
For the aromatization, if appropriate, mild oxidizing agents, such as elemental sulphur of preferably chalcones, are employed. Chalcones are xcex1,xcex2-unsaturated ketones of the type C6H5xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94C6H5. The terminal phenyl radicals may in each case carry one or more substituents, selected from the group consisting of halogen, trifluoromethyl, straight-chain or branched alkyl having up to 4 carbon atoms. Preference is given, for example, to using the chalcone 4xe2x80x94CF3-C6H4-COxe2x80x94CHxe2x95x90CHxe2x80x94C6H4xe2x80x944xe2x80x94F.
The subsequent reduction of the keto group is carried out regio- and enantio-selectively, for example using a borane/diethylaniline complex with addition of a chiral aminoalcohol, such as 1-aminoindan-2-ol, in anhydrous ethers, in particular THF, under protective gas at temperatures of from xe2x88x9270xc2x0 C. to 50xc2x0 C.
The hydroxyl group that is formed is protected by a trialkylsilyl group, for example by the tert-butyldimethylsilyl group. The introduction is carried out via the customary active silyl derivates, for example the chlorides or the trifluoromethanesulphonate (triflates), in the presence of sterically hindered bases, such as, for example, lutidine, at temperatures of from xe2x88x9220xc2x0 C. to 0xc2x0 C. in inert solvents, such as toluene, under an atmosphere of protective gas.
The second keto function can be reduced by customary methods, for example using lithium aluminium hydride in ethers, in particular in THF, at temperatures of from 0xc2x0 C. to 50xc2x0 C. The desired diastereomer can be isolated from the resulting mixture of diastereomers, for example, by chromatography.
Details of the other possible reactions of the compounds of the formula (XXIII), such as, for example, removal of the silyl protective groups or introduction of a fluoro substituent into the substituent D, are given elsewhere.
The compounds of the general formula (II) are novel and can be prepared, for example, by converting compounds of the general formula (XXV) 
in which
R1xe2x80x3 and R2xe2x80x3 each represent a straight-chain or branched alkylene chain having up to 7 carbon atoms,
xe2x80x83and
R45 and R46 are identical or different and each represents straight-chain or branched alkyl having up to 4 carbon atoms,
by 2-fold reaction according to the literature [M. Yamagushi et al., J. Org. Chem. 55, p. 1611-1623, 1990; cf. also, for example, M. Yamagushi, Tetrahedron Lett. 27, 21, 1986, 2401-2404] with compounds of the general formula (XXVI) 
xe2x80x83in which
R35 is as defined above,
into the compounds of the general formula (XXVII) 
xe2x80x83in which
R35 is as defined above
xe2x80x83and
R1xe2x80x2xe2x80x3 and R2xe2x80x2xe2x80x3 have the meanings of R1xe2x80x3 and R2xe2x80x3 given above, where the alkylene chain is substituted by a carbonyl group,
and subsequently converting these by action of Tf2O/pyridine and reaction in a further step with compounds of the general formula (XXVIII)
Axe2x80x94B(OH)2xe2x80x83xe2x80x83(XXVIII)
xe2x80x83in which
A is as defined above,
in inert solvents and in the presence of a palladium complex into the compounds of the general formula (XXIX) 
xe2x80x83in which
R35, R1xe2x80x2xe2x80x3 and R2xe2x80x2xe2x80x3 are each as defined above,
reducing the carbonyl function to give the hydroxyl function, blocking this by reaction with TBSOTf and subsequently carrying out an alkylation with compounds of the general formula (XXX)
xe2x80x83Exe2x80x2xe2x80x3xe2x80x94Ixe2x80x83xe2x80x83(XXX)
xe2x80x83in which
Exe2x80x2xe2x80x3 has the scope of meanings of Exe2x80x2 and Exe2x80x3 given above.
The introduction of substituent A is generally carried out in 2 steps, initially reacting with Tf2O in pyridine. The reaction with the compounds of the general formula (XXVIII) is carried out in a further step.
Solvents which are suitable for all processes are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to employ mixtures of the abovementioned solvents. Preference is given to dioxane.
Suitable palladium compounds in the context of the present invention are generally PdCl2((C6H5)3)2, palladium-bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis-(diphenylphosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl2) or Pd(P(C6H5)3)4. Preference is given to Pd(P(C6H5)3)4.
The reaction is generally carried out in a temperature range of from room temperature to +150xc2x0 C., preferably of from +40xc2x0 C. to +110xc2x0 C.
The reaction is generally carried out at atmospheric pressure. However, it is also possible to carry out the process at reduced pressure or at elevated pressure (for example in the range of from 0.5 to 5 bar).
The reduction of the compounds of the general formula (XIV) is generally carried out in one of the abovementioned solvents, preferably using DIBAH.
The reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of ketones to give hydroxyl compounds. Particularly suitable in this context is the reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborohydride. The reduction is preferably carried out using complex metal hydrides, such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium-trialkylborohydride, diisobutylaluminium hydride or lithium aluminium hydride. Very particularly preferably, the reduction is carried out using diisobutylaluminium hydride and sodium borohydride.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably of from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds in a temperature range of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably of from xe2x88x9278xc2x0 C. to 0xc2x0 C. in the case of DIBAH, of from 0xc2x0 C. to room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of the reducing agent and the solvent.
The reduction generally proceeds at atmospheric pressure, but is also possible to carry out the reduction at elevated or reduced pressure.
The subsequent introduction of the TBS group is carried out in one of the abovementioned solvents, preferably using toluene, in a temperature range of from xe2x88x9230xc2x0 C. to room temperature, preferably of from xe2x88x9220xc2x0 C. to 0xc2x0 C., and at atmospheric pressure.
The alkylation with alkyl halides is generally carried out in inert solvents in the presence of a base.
Solvents which are suitable for this purpose are, depending on the nature of the alkylating agent, all inert organic solvents. These preferably include ethers, such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons, such as benzene, toluene or xylene, or dimethylformamide or hexamethylphosphoric triamide, or mixtures of the abovementioned solvents.
Bases which are suitable for the alkylation are the customary basic compounds. These preferably include alkali metal hydrides, such as sodium hydride, alkali metal amides, such as sodium amide or lithium diisopropylamide, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, such as trialkylamines, for example triethylamine, or organolithium compounds, such as butyllithium or phenyllithium. Preference is given to lithium diisopropylamide.
The alkylation is generally carried out in a temperature range of from xe2x88x9270xc2x0 C. to +80xc2x0 C., preferably of from xe2x88x9270xc2x0 C. to 0xc2x0 C.
The alkylation is generally carried out at atmospheric pressure. However, it is also possible to carry out the process at reduced pressure or elevated pressure (for example in the range of from 0.5 to 5 bar).
The compounds of the general formulae (III), (XXV), (XXVI), (XXVII), (XXVIII) and (XXX) are known per se or can be prepared by customary methods.
The compounds of the general formula (XXIX) are novel and can be prepared as described above.
The compounds of the general formula (IV) are novel and can be prepared as described above.
The compounds of the general formula (VIII) are novel and can be prepared as described above.
The compounds of the general formula (VI) are novel and can be prepared by reacting compounds of the general formula (Va) 
in which
A, E, R1xe2x80x2 and R2xe2x80x2 are each as defined above,
under an atmosphere of protective gas in inert solvents with one of the abovementioned oxidizing agents in the presence of a base, preferably using the SO3/pyridine complex.
Solvents which are suitable for the individual steps are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, diisopropyl ether or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene. It is also possible to employ mixtures of the abovementioned solvents.
The oxidizing agent is employed in an amount of from 1 mol to 10 mol, preferably of from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (Va).
The bases which are suitable for the individual steps are the customary basic compounds. These preferably include pyridine or organolithium compounds, such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Particular preference is given to using pyridine.
The base is employed in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (Va).
The oxidation generally proceeds at a temperature of from xe2x88x9250xc2x0 C. to +100xc2x0 C., preferably of from 0xc2x0 C. to room temperature.
The compounds of the general formulae (V), (VIII) and (IX) are novel and can be prepared by converting compounds of the general formula (XXXI) 
in which
A, R1xe2x80x2xe2x80x3 and R2xe2x80x2xe2x80x3 are each as defined above,
xe2x80x83and
R47 either represents the radical of the formula 
xe2x80x83in which R35, R38, R7xe2x80x2 and R8xe2x80x2 are each as defined above,
initially by acid hydrolysis with aqueous citric acid solution into the compounds of the general formula (XXXII) 
xe2x80x83in which
A, R1xe2x80x2xe2x80x3,R2xe2x80x2xe2x80x3 and R47 are each as defined above,
subsequently carrying out an oxidation in inert solvents to give the compounds of the general formula (XXXIII) 
xe2x80x83in which
A, R1xe2x80x2xe2x80x3,R2xe2x80x2xe2x80x3 and R47 are each as defined above,
preparing, in a further step, the compounds of the general formula (XXXIV) 
xe2x80x83in which
A, R1xe2x80x2xe2x80x3, R2xe2x80x2xe2x80x3 and R47 are each as defined above,
by reaction with trifluoromethanesulphonic anhydride in pyridine, followed by reaction with compounds of the general formula (XXXV)
EIVxe2x80x83xe2x80x83(XXXV)
xe2x80x83in which
EIV represents cycloalkenyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkenyl having up to 8 carbon atoms, or represents a radical of the formula xe2x80x94R48xe2x80x94Sn(R49R50R51),
xe2x80x83in which
R48 represents straight-chain or branched alkenyl having up to 8 carbon atoms,
R49, R50 and R51 are identical or different and each represents straight-chain or branched alkyl having up to 8 carbon atoms,
in the system Pd(dba)2/1,2-bis(diphenylphosphino)ethane, Pd(PPh3)4, PdCl2(PPh3)2 and LiCl in the presence of an inert solvent and a base under elevated pressure and an atmosphere of protected gas to give the compounds of the general formula (XXXVI) 
xe2x80x83in which
A, EIV, R1xe2x80x2xe2x80x3,R2xe2x80x2xe2x80x3 and R47 are each as defined above,
carrying out a hydrogenation in the presence of a catalyst to give the compounds of the general formula (XXXVII) 
xe2x80x83in which
A, E, R1xe2x80x2xe2x80x3,R2xe2x80x2xe2x80x3 and R47 are each as defined above,
carrying out, in a further step, the selective reduction of the carbonyl group (R1xe2x80x3/R2xe2x80x3) in ethers to give the compounds of the general formula (XXXVIII) 
xe2x80x83in which
A, E and R47 are each as defined above
xe2x80x83and
R1IV and R2IV each have the meaning of R1xe2x80x2 and R2xe2x80x2 given above, the alkylene chain being substituted by hydroxyl,
and subsequently converting these by protection of the free hydroxyl function with tert-butyldimethylsilyl triflate (TBS) in inert solvents into the compounds of the general formula (XXXIX) 
xe2x80x83in which
A, E, R1xe2x80x2, R2xe2x80x2 and R47 are each as defined above,
and, in the case R38=CO2R35, selectively reducing the alkoxycarbonyl function by customary methods to give the hydroxymethyl function.
The reaction of the compounds of the general formula (XVI) is carried out using aqueous solutions of customary acids at a temperature of from 0xc2x0 C. to 150xc2x0 C., preferably using carboxylic acids, such as citric acid and oxalic acid, at 60xc2x0 C. and at atmospheric pressure.
The oxidation to give the compounds of the general formula (XXXIII) is, in the context of the present invention, carried out under the following conditions: Solvents which are suitable for the oxidation are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to employ mixtures of the abovementioned solvents. Preference is given to toluene.
Suitable oxidizing agents are, for example, cerium(IV) ammoniumnitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmium tetroxide, sodium acetate/iodine and manganese dioxide. Preference is given to 2,3-dichloro-5,6-dicyano-benzoquinone.
The oxidizing agent is employed in an amount of from 1 mol to 10 mol, preferably of from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (XXXIII).
The oxidation generally proceeds in a temperature range of from 0xc2x0 C. to +100xc2x0 C., preferably of from room temperature to 80xc2x0 C.
The oxidation generally proceeds at atmospheric pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
The hydroxyl protective group trifluoromethanesulphonyl is generally introduced into the compounds of the general formula (XXXIII) in pyridine using trifluoromethanesulphonic anhydride in a temperature range of from xe2x88x9230xc2x0 C. to +40xc2x0 C., preferably of from xe2x88x9220xc2x0 C. to 0xc2x0 C., and at atmospheric pressure.
The reaction with the compounds of the general formula (XXXV) is carried out in the case of the olefins in a Heck reaction in an autoclave using a phosphino and palladium complex, in the presence of an inert solvent and a base under an atmosphere of nitrogen, in a temperature range of from +80xc2x0 C. to +120xc2x0 C., preferably at 100xc2x0 C., or, in the case of the alkenylstannyl compounds, at from room temperature to 100xc2x0 C.
Suitable solvents are the abovementioned cyclic hydrocarbons and ethers, and preference is given to toluene and dioxane.
Suitable bases are the abovementioned dialkylamines, preferably ethyldiisopropylamine.
The base is generally employed in an amount of from 0.5 mol to 5 mol, preferably of from 1 mol to 3 mol, based on 1 mol of the compounds of the general formula (XXXV).
Suitable palladium compounds in the context of the present invention are generally PdCl2((C6H5)3)2, palladium-bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis-(diphenylphosphino)ferrocene]-palladium(II)chloride (Pd(dppf)Cl2), Pd(P(C6H5)3)4, Pd(PPh3)3, Pd(Oac)2, if appropriate with addition of phosphineligands (for example dppe, diphos, dba, chiraphor, etc.)
The reduction of the double bond in the radical Exe2x80x2xe2x80x3 is generally carried out by hydrogenation.
The hydrogenation is carried out by customary methods using hydrogen in the presence of noble metal catalysts, such as, for example Pd/C, Pt/C or Raney nickel, in one of the abovementioned solvents, preferably in alcohols, such as, for example, methanol, ethanol or propanol, in a temperature range of from xe2x88x9220xc2x0 C. to +100xc2x0 C., preferably of from 0xc2x0 C. to +50xc2x0 C., at atmospheric pressure or superatmospheric pressure.
The reduction to give the compounds of the general formula (XXXVIII) is generally carried out in one of the abovementioned ethers, preferably in tetrahydrofuran, in a temperature range of from 0xc2x0 C. to +40xc2x0 C., preferably of from 0xc2x0 C. to room temperature, and at atmospheric pressure.
Suitable reducing agents are generally aluminium hydrides, such as LiAlH4, DIBAH, Red-Al; boron hydrides, such as NaBH4, NaCNBH3, LiBH4; borane complexes, such as BH3xc3x97THF, BH3xc3x97DMS, BH3xc3x97(Et2)NC6H5 or borane-dimethyl sulphide solution in tetrahydrofuran. Preference is given to borane-dimethyl sulphide solution in tetrahydrofuran. For stereoselective reductions, the borane complexes can be combined with chiral auxiliaries, such as chiral amino alcohols; preference is given here to chiral aminoindanol, for example 1R,2S-aminoindanol.
The TBS group for blocking the hydroxyl function is generally introduced in toluene using tert-butyl-dimethylsilyl triflate and a base, preferably 2,6-lutidine, in a temperature range of from xe2x88x9230xc2x0 C. to +10xc2x0 C., preferably of from xe2x88x9220xc2x0 C. to 0xc2x0 C. and at atmospheric pressure.
The reduction of the compounds of the general formula (XXXIX) is generally carried out in ether, THF or in one of the abovementioned cyclic hydrocarbons, preferably in toluene, in a temperature range of from xe2x88x9278xc2x0 C. to xe2x88x9220xc2x0 C., preferably of from xe2x88x9278xc2x0 C. to xe2x88x9240xc2x0 C., and at atmospheric pressure.
The reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of ketones to hydroxyl compounds. Particularly suitable here is the reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out using complex metal hydrides, such as, for example, lithium borohydride; sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, diisobutylaluminium hydride or lithium aluminium hydride. Very particularly preferably, the reduction is carried out using diisobutylaluminium hydride and sodium borohydride.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably of from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction is generally carried out in a temperature range of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably of from xe2x88x9278xc2x0 C. to 0xc2x0 C. in the case of DIBAH, of from 0xc2x0 C. to room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of the reducing agent and the solvent.
The reduction generally proceeds at atmospheric pressure, but it is also possible to carry out the reaction under elevated or reduced pressure.
The compounds of the general formulae (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX) are novel and can be prepared as described above.
The compounds of the general formula (XXXV) are known.
The compounds of the general formula (XXXI) are novel and can be prepared by reacting dimedone with compounds of the general formula (XL)
Axe2x80x94CHOxe2x80x83xe2x80x83(XL)
in which
A is as defined above
and compounds of the general formula (XLI) 
xe2x80x83in which
R47 is as defined above,
in saturated cyclic hydrocarbons, preferably cyclohexane, under reflux and at atmospheric pressure.
The compounds of the general formulae (XL) and (XLI) are known or can be prepared by customary methods.
The compounds of the general formula (X) can be prepared similarly to the process which is described below by way of example for the compound spiro[2,5]non-7-en-3-one.
Starting from cyclobutyl-dimedone(spiro[3,5]nonane-6,8-dione) of the formula (XLII) 
reaction with p-toluenesulphonic acid (PTA) in toluene and isobutanol and subsequent reduction with Red-Al in toluene gives the compound spiro[2,5]non-7-en-3-one of the formula (XLIII) 
The reaction with PTA/isobutanol is carried out with azeotropic distillation.
The reaction is carried out in a temperature range of from 0xc2x0 C. to 60xc2x0 C., preferably of from 20xc2x0 C. to 50xc2x0 C. Both reaction steps are carried out at atmospheric pressure.
The reaction can pass through the following intermediate stages: 
The preparation of the compound of the formula (XLII) is carried out by initially preparing, by reaction of cyclobutanone with triphenylphosphoranylidene-2-propanone and benzoic acid, the compound cyclobutylidene-2-propanone of the formula (XLVI) 
and finally reacting with dimethyl malonate or diethyl malonate, if appropriate via the sequence of non-isolated intermediates of the formulae 
and subsequently carrying out a decarboxylation.
The preparation of the compound of the formula (XLVI) is carried out in a temperature range of from 80xc2x0 C. to 120xc2x0 C. and at atmospheric pressure.
The reaction with the appropriate malonic acid diesters is carried out in methanol or ethanol and at atmospheric pressure and at reflux temperature.
The preparation of the compounds of the general formula (XIII) is carried out by reacting the compounds of the formula (LII) 
in which
R6 is as defined above
and compounds of the general formula (LIII) 
xe2x80x83in which
A is as defined above,
in methylcyclohexane and in the presence of conc. sulphuric acid at reflux temperature and at atmospheric pressure.
The compounds of the general formulae (LII) and (LIII) are known and can be prepared by customary methods.
The compounds of the general formula (I) according to the invention have a pharmacological activity spectrum which could not have been foreseen.
The compounds of the general formula (I) according to the invention have useful pharmacological properties which are superior when compared to the prior art, in particular, they are highly effective inhibitors of the cholesterol ester transfer protein (CETP) and they stimulate the reverse cholesterol transport. The active compounds according to the invention effect a reduction of the LDL cholesterol level in the blood and simultaneously increase the HDL cholesterol level. They can therefore be used for the treatment and prevention of hypoalphalipoproteinaemia, dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias or arteriosclerosis.
The pharmacological activity of the substances according to the invention was assessed using the following test:
CETP Inhibition Test
Preparation of CETP
CETP is obtained in partially purified form from human plasma by differential centrifugation and column chromatography and used for the test. For this purpose, human plasma is adjusted to a density of 1.21 g per ml using NaBr and centrifuged at 50,000 rpm at 4xc2x0 C. for 18 h. The bottom fraction (d greater than 1.21 g/ml) is applied to a Sephadex(copyright)Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 mM NaCl/0.001 M TrisHCl pH 7.4 and subsequently eluted using dist. water. The CETP-active fractions are pooled, dialysed against 50 mM Na-acetate pH 4.5 and applied to a CM-Sepharose(copyright) (Pharmacia) column. Elution is subsequently carried out using a linear gradient (0-1 M NaCl). The pooled CETP fractions are dialysed against 10 mM TrisHCl pH 7.4 and subsequently purified further by chromatography over a Mono Q(copyright) column (Pharmacia).
Preparation of Radioactively Labelled HDL
50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 using NaBr and centrifuged at 4xc2x0 C. in a Ty 65 rotor at 50,000 rpm for 18 h. The upper phase is used to obtain cold LDL. The lower phase is dialysed against 3*4 l of PDB buffer (10 mM Tris/HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3). Per 10 ml volume of retained material, 20 xcexcl of 3H-cholesterol (Dupont NET-725; 1 xcexcCi/ml, dissolved in ethanol!) are subsequently added, and the mixture is incubated at 37xc2x0 C. under N2 for 72 h.
The mixture is then adjusted to a density of 1.21 using NaBr and centrifuged in a Ty 65 rotor at 20xc2x0 C. and 50,000 rpm for 18 h. The upper phase is collected and the lipoprotein fractions are purified by gradient centrifugation. To this end, the isolated labelled lipoprotein fraction is adjusted to a density of 1.26 using NaBr. In each case 4 ml of this solution are covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution of a density of 1.21 and 4.5 ml of a solution of 1.063 (density solutions of PDB buffer and NaBr), and the tubes are subsequently centrifuged in an SW 40 rotor at 38,000 rpm and 20xc2x0 C. for 24 h. The intermediate layer which is found between a density of 1.063 and a density of 1.21 and which contains the labelled HDL is dialysed against 3*100 volume of PDB buffer at 4xc2x0 C.
The retained material contains radioactively labelled 3H-CE-HDL, which is used for the test adjusted to approximately 5xc3x97106 cmp.
CETP Test
To assess the CETP activity, the transfer of 3H-cholesterol ester from human HD-lipoproteins to biotinylated LD-lipoproteins is measured.
The reaction is terminated by addition of Streptavidin-SPA(copyright) beads (Amersham) and the transferred radioactivity is directly measured in a liquid scintillation counter.
In the assay mixture, 10 xcexcl of HDL-3H-cholesterol ester (xcx9c50,000 cpm) with 10 xcexcl of Biotin-LDL (Amersham) in 50 mM Hepes/0.15 m NaCl/0.1% bovine serum albumin/0.05% NaN3 pH 7.4 are incubated with 10 xcexcl of CETP (1 mg/ml) and 3 xcexcl of a solution of the substance to be tested (dissolved in 10% DMSO/1% BSA) at 37xc2x0 C. for 18 h. 200 xcexcl of the SPA streptavidin bead solution (TRKQ 7005) are subsequently added, the mixture is incubated with shaking for another 1 h and subsequently measured in a scintillation counter. The controls used are corresponding incubations with 10 xcexcl of buffer, 10 xcexcl of CETP at 4xc2x0 C. and 10 xcexcl of CETP at 37xc2x0 C.
The activity which is transferred in the control experiments with CETP at 37xc2x0 C. is taken to be 100% transfer. The substance concentration at which this transfer is reduced by half is stated as the IC50 value.
In Table A below, the IC50 values (mol/l) for CETP inhibitors are given:
Ex vivo Activity of the Compounds According to the Invention
Syrian gold hamsters, which have been bred in our own laboratory, are anaesthetized after 24 hours of fasting (0.8 mg/kg of atropine, 0.8 mg/kg of Ketavet(copyright) s.c., 30xe2x80x2 later 50 mg/kg of nembutal i.p.). The jugular vein is subsequently exposed and cannulated. The test substance is dissolved in a suitable solvent (usually adalate placebo solution: 60 g of glycerol, 100 ml of H2O, ad 1000 ml PEG-400) and administered to the animals via a PE catheter, which is introduced into the jugular vein. The same volume of solvent without test substance is administered to the control animals. The vein is subsequently tied off and the wound is closed.
The test substances can also be administered p.o. by dissolving the substances in DMSO and suspending them in 0.5% tylose and administering them using a pharyngeal tube. Identical volumes of solvent without test substance are administered to the control animals.
At different intervalsxe2x80x94up to 24 hours after the administrationxe2x80x94blood samples are taken from the animals by puncture of the retro-orbital venous plexus (approximately 250 xcexcl). Coagulation is completed by incubation at 4xc2x0 C. overnight, and the samples are subsequently centrifuged at 6000xc3x97g for 10 minutes. The CETP activity is determined in the resulting serum using the modified CETP test. The transfer of 3H-cholesterol ester from HD-lipoproteins to biotinylated LD-lipoproteins is measured as described above for the CETP test.
The reaction is terminated by addition of Streptavidin-SPA(copyright) beads (Amersham), and the transferred radioactivity is directly determined in a liquid scintillation counter.
The test protocol is carried out as described under xe2x80x9cCETP testxe2x80x9d. However, to test the sera, 10 xcexcl of CETP are replaced by 10 xcexcl of the appropriate serum samples. Corresponding incubations of sera of untreated animals serve as controls.
The activity that is transferred in the control experiments using control sera is classified as 100% transfer. The substance concentration at which this transfer is reduced by half is stated as the ED50 value.
In vivo Activity of the Compounds According to the Invention
In experiments for assessing the oral activity on lipoproteins and triglycerides, test substance, dissolved in DMSO and suspended in 0.5% tylose, is administered perorally by means of a pharyngeal tube to Syrian gold hamsters which have been bred in our own laboratory. To determine the CETP activity, blood samples (approximately 250 xcexcl) are taken by retro-orbital puncture prior to the start of the experiment. The test substances are subsequently administered perorally using a pharyngeal tube. Identical volumes of solvent without test substance are administered to the control animals. Subsequently, the animals have to fast and at different intervalsxe2x80x94up to 24 hours after the administration of the substancesxe2x80x94blood samples are taken by puncture of the retro-orbital venous plexus.
Coagulation is completed by incubation at 4xc2x0 C. overnight, and the samples are subsequently centrifuged at 6000xc3x97g for 10 minutes. The content of cholesterol and triglycerides in the resulting serum is assessed using modified commercially available enzyme tests (cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum is diluted in a suitable manner with normal saline solution.
100 xcexcl of serum dilution and 100 xcexcl of test substance are transferred into 96-well-plates and incubated at room temperature for 10 minutes. The optical density is subsequently determined at a wavelength of 492 nm using an automatic plate reader.
The triglyceride and cholesterol concentrations of the samples are determined with the aid of a standard curve measured in parallel.
The determination of the HDL-cholesterol content is carried out after precipitation of the ApoB-containing lipoproteins using a reagent mixture (Sigma 352-4 HDL cholesterol reagent) in accordance with the instructions of the manufacturer.
In vivo Activity in Transgenic hCETP Mice
The substances to be tested were administered to transgenic mice, which were bred in our own laboratory (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301), via the feed. Prior to the beginning of the experiment, blood samples were taken retro-orbitally from the mice to determine cholesterol and triglycerides in the serum. The serum was obtained as described above for hamsters by incubation at 4xc2x0 C. overnight and subsequent centrifugation at 6000xc3x97g. After one week, blood samples were again taken from the mice to determine lipoproteins and triglycerides. The change of the measured parameters are expressed as a change in percent based on the initial value.
The invention furthermore relates to the combination of substituted tetrahydro-naphthalenes of the general formula (I) with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidaemias, of obesity (adipositas) and of diabetes mellitus. Glucosidase and/or amylase inhibitors in the context of the present invention are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.
Preference is given to the combination of acarbose, miglitol, emiglitate or voglibose with one of the abovementioned compounds of the general formula (I) according to the invention.
Furthermore, the compounds according to the invention can be combined with cholesterol-lowering vastatines or ApoB-lowering principles, in order to treat dyslipidaemias, combined hyperlipidaemias, hypercholesterolaemias or hypertriglyceridaemias.
The abovementioned combinations can also be used for primary or secondary prevention of coronary heart diseases (for example myocardial infarction).
Vastatines in the context of the present invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. ApoB-lowering agents are, for example, MTP inhibitors.
Preference is given to the combination of cerivastatin or ApoB inhibitors with one of the abovementioned compounds of the general formulae (I) and (Ia) according to the invention.
The novel active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. In this case the therapeutically active compound should in each case be present in a concentration from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compound using solvents and/or carriers, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration is carried out in a customary manner, intravenously, orally, parenterally or perlingually, in particular orally.
In the case of parenteral administration, solutions of the active compound can be used by employing suitable liquid carrier materials.
In general, it has proved advantageous, in the case of intravenous administration, to administer amounts from approximately 0.01 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration the dosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration route, on individual reaction towards the medicament, the manner of its formulation and the time at or interval during which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.